Targeting microbubbles-carrying TGFβ1 inhibitor combined with ultrasound sonication induce BBB/BTB disruption to enhance nanomedicine treatment for brain tumors
Journal
Journal of Controlled Release
Journal Volume
211
Pages
53-62
Date Issued
2015
Author(s)
Abstract
The clinical application of chemotherapy for brain cancer tumors remains a challenge due to difficulties in the transport of therapeutic agents across the blood-brain barrier/blood-tumor barrier (BBB/BTB). In this study, we developed des-octanoyl ghrelin-conjugated microbubbles (GMB) loaded with TGFβ1 inhibitor (LY364947) (GMBL) to induce BBB/BTB disruption for ultrasound (US) sonication with GMBL. The in-vitro stability study showed that GMB was pretty stable over one month. The in-vivo study showed that the accumulation of superparamagnetic iron oxide nanoparticles (SPION) in the sonicated tumor was significantly higher for focused US sonication in the presence of GMBL, indicating that GMBL/US can locally disrupt BBB/BTB to promote vascular permeability of nanoparticles. In addition, the combination of folate-conjugated polymersomal doxorubicin (FPD) and GMBL/US (FPD + GMBL/US) achieved the best anti-glioma effect and significant improvement in the overall survival time for brain tumor-bearing mice. When combined with focused US, GMBL facilitated local BBB/BTB disruption and simultaneously released LY364947 to decrease the pericyte coverage of the endothelium at the targeted brain tumor sites, resulting in enhanced accumulation and antitumor activity of FPD. The overall results indicate that GMBL/US owns a great potential for non-invasive targeting delivery of nanomedicine across the BBB to treat central nervous system (CNS) diseases. ? 2015 Elsevier B.V. All rights reserved.
Subjects
Bloodbrain/bloodtumor barrier (BBB/BTB); Des-octanoyl ghrelin; Folate; Microbubbles; Targeted delivery; TGFβ1 inhibitor; Ultrasound
SDGs
Other Subjects
Chemotherapy; Medical nanotechnology; Nanoparticles; Sonication; Tumors; Ultrasonics; Bloodbrain/bloodtumor barrier (BBB/BTB); Folate; Ghrelin; Microbubbles; Targeted delivery; Brain; doxorubicin; folic acid; ghrelin; ly 364947; protein inhibitor; superparamagnetic iron oxide nanoparticle; transforming growth factor beta 1 inhibitor; unclassified drug; Ly-364947; pyrazole derivative; pyrrole derivative; Tgfb1 protein, mouse; transforming growth factor beta1; animal cell; animal experiment; animal model; animal tissue; antineoplastic activity; Article; blood brain barrier; blood tumor barrier; blood vessel permeability; brain tumor; controlled study; drug conjugation; drug delivery system; drug efficacy; endothelium; glioma; in vitro study; in vivo study; male; microbubble; mouse; nanomedicine; nonhuman; overall survival; pericyte; priority journal; rat; survival time; ultrasound; animal; antagonists and inhibitors; blood brain barrier; Brain Neoplasms; capillary permeability; drug effects; Institute for Cancer Research mouse; metabolism; nanomedicine; physiology; procedures; SCID mouse; Sprague Dawley rat; ultrasound; Animals; Blood-Brain Barrier; Brain Neoplasms; Capillary Permeability; Drug Delivery Systems; Male; Mice; Mice, Inbred ICR; Mice, SCID; Microbubbles; Nanomedicine; Pyrazoles; Pyrroles; Rats; Rats, Sprague-Dawley; Sonication; Transforming Growth Factor beta1
Type
journal article